Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults

Jenny van Dongen; Nuno R Zilhão; Karen Sugden; Eilis J Hannon; Jonathan Mill; Avshalom Caspi; Jessica Agnew-Blais; Louise Arseneault; David L Corcoran; Terrie E Moffitt; Richie Poulton; Barbara Franke; D.I. Boomsma; BIOS Consortium

doi:10.1016/j.biopsych.2019.02.016

Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults

Jenny van Dongen^*
, Nuno R Zilhão
, Karen Sugden
, Eilis J Hannon
, Jonathan Mill
, Avshalom Caspi
, Jessica Agnew-Blais
, Louise Arseneault
, David L Corcoran
, Terrie E Moffitt
, Richie Poulton
, Barbara Franke
, D.I. Boomsma
, BIOS Consortium

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

BACKGROUND: Previous studies have reported associations between attention-deficit/hyperactivity disorder symptoms and DNA methylation in children. We report the first epigenome-wide association study meta-analysis of adult attention-deficit/hyperactivity disorder symptoms, based on peripheral blood DNA methylation (Infinium HumanMethylation450K array) in three population-based adult cohorts.

METHODS: An epigenome-wide association study was performed in the Netherlands Twin Register (N = 2258, mean age 37 years), Dunedin Multidisciplinary Health and Development Study (N = 800, age 38 years), and Environmental Risk Longitudinal Twin Study (N = 1631, age 18 years), and results were combined through meta-analysis (total sample size N = 4689). Region-based analyses accounting for the correlation between nearby methylation sites were also performed.

RESULTS: One epigenome-wide significant differentially methylated position was detected in the Dunedin study, but meta-analysis did not detect differentially methylated positions that were robustly associated across cohorts. In region-based analyses, six significant differentially methylation regions (DMRs) were identified in the Netherlands Twin Register, 19 in the Dunedin study, and none in the Environmental Risk Longitudinal Twin Study. Of these DMRs, 92% were associated with methylation quantitative trait loci, and 68% showed moderate to large blood-brain correlations for DNA methylation levels. DMRs included six nonoverlapping DMRs (three in the Netherlands Twin Register, three in the Dunedin study) in the major histocompatibility complex, which were associated with expression of genes in the major histocompatibility complex, including C4A and C4B, previously implicated in schizophrenia.

CONCLUSIONS: Our findings point at new candidate loci involved in immune and neuronal functions that await further replication. Our work also illustrates the need for further research to examine to what extent epigenetic associations with psychiatric traits depend on characteristics such as age, comorbidities, exposures, and genetic background.

Original language	English
Pages (from-to)	599-607
Number of pages	9
Journal	Biological Psychiatry
Volume	86
Issue number	8
Early online date	1 Mar 2019
DOIs	https://doi.org/10.1016/j.biopsych.2019.02.016
Publication status	Published - 15 Oct 2019

Bibliographical note

Funding

Dunedin study: The Dunedin Multidisciplinary Health and Development Research Unit was supported by the New Zealand Health Research Council and New Zealand Ministry of Business, Innovation and Employment, and also by the National Institutes of Health National Institute of Aging (Grant No. R01AG032282 ), Medical Research Council (Grant No. MR/P005918 ), and Jacobs Foundation . This work used a high-performance computing facility partially supported by Grant No. 2016-IDG-1013 (“HARDAC+: Reproducible HPC for Next-generation Genomics”) from the North Carolina Biotechnology Center . NTR: NTR was supported by Biobanking and Biomolecular Research Infrastructure, the Netherlands (BBMRI-NL), Netherlands Organisation for Scientific Research (NWO) 480-15-001/674, Netherlands Twin Registry Repository: researching the interplay between genome and environment (NWO 184.021.007), and Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies (ACTION). ACTION receives funding from the European Union Seventh Framework Program (FP7/2007-2013) (Grant No. 602768). NTR was also supported by the Royal Netherlands Academy of Science Professor Award (Grant No. PAH/6635 to DIB), Netherlands Organization for Scientific Research (Vici Grant No. 016-130-669 to BF), Dutch National Science Agenda for the NWANeurolabNL project (Grant No. 400 17 602 to BF), European Community FP7 (Grant No. 602805 [Aggressotype] to BF), and European Community Horizon 2020 Program (H2020/2014?2020) (Grant No. 728018 [Eat2beNICE] to BF). Dunedin study: The Dunedin Multidisciplinary Health and Development Research Unit was supported by the New Zealand Health Research Council and New Zealand Ministry of Business, Innovation and Employment, and also by the National Institutes of Health National Institute of Aging (Grant No. R01AG032282), Medical Research Council (Grant No. MR/P005918), and Jacobs Foundation. This work used a high-performance computing facility partially supported by Grant No. 2016-IDG-1013 (?HARDAC+: Reproducible HPC for Next-generation Genomics?) from the North Carolina Biotechnology Center. E-Risk study: The E-Risk study was supported by the Medical Research Council (Grant No. G1002190), National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant No. HD077482), American Asthma Foundation Distinguished Investigator Award (to JM), Jacobs Foundation, Avielle Foundation, Economic and Social Research Council Mental Health Leadership Fellowship (to LA), and Medical Research Council Skills Development Fellowship (to JA-B). This work used a high-performance computing facility partially supported by Grant No. 2016-IDG-1013 (?HARDAC+: Reproducible HPC for Next-generation Genomics?) from the North Carolina Biotechnology Center. NTR: We thank the twins and their family members for their participation. Dunedin study: We thank the Dunedin Study members, unit research staff, and study founder Phil Silva. E-Risk study: We thank the study families for their participation and members of the E-Risk team for their dedication, hard work, and insights. The HumanMethylation450K BeadChip and RNA sequencing data from the BIOS Consortium are available in the European Genome-phenome Archive, under accession code EGAD00010000887. Data from the Dunedin Multidisciplinary Health and Development are available via a managed access system (contact: [email protected]). The HumanMethylation450K BeadChip DNA methylation data from the E-Risk study are available in Gene Expression Omnibus under accession number GSE105018. BF has received educational speaking fees from Shire and MEDICE. The other authors report no biomedical financial interests or potential conflicts of interest. NTR: NTR was supported by Biobanking and Biomolecular Research Infrastructure, the Netherlands (BBMRI-NL), Netherlands Organisation for Scientific Research (NWO) 480-15-001/674, Netherlands Twin Registry Repository: researching the interplay between genome and environment (NWO 184.021.007), and Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies (ACTION). ACTION receives funding from the European Union Seventh Framework Program (FP7/2007-2013) (Grant No. 602768). NTR was also supported by the Royal Netherlands Academy of Science Professor Award (Grant No. PAH/6635 to DIB), Netherlands Organization for Scientific Research (Vici Grant No. 016-130-669 to BF), Dutch National Science Agenda for the NWANeurolabNL project (Grant No. 400 17 602 to BF), European Community FP7 (Grant No. 602805 [Aggressotype] to BF), and European Community Horizon 2020 Program (H2020/2014–2020) (Grant No. 728018 [Eat2beNICE] to BF). Dunedin study: The Dunedin Multidisciplinary Health and Development Research Unit was supported by the New Zealand Health Research Council and New Zealand Ministry of Business, Innovation and Employment, and also by the National Institutes of Health National Institute of Aging (Grant No. R01AG032282), Medical Research Council (Grant No. MR/P005918), and Jacobs Foundation. This work used a high-performance computing facility partially supported by Grant No. 2016-IDG-1013 (“HARDAC+: Reproducible HPC for Next-generation Genomics”) from the North Carolina Biotechnology Center. E-Risk study: The E-Risk study was supported by the Medical Research Council (Grant No. G1002190), National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant No. HD077482), American Asthma Foundation Distinguished Investigator Award (to JM), Jacobs Foundation, Avielle Foundation, Economic and Social Research Council Mental Health Leadership Fellowship (to LA), and Medical Research Council Skills Development Fellowship (to JA-B). This work used a high-performance computing facility partially supported by Grant No. 2016-IDG-1013 (“HARDAC+: Reproducible HPC for Next-generation Genomics”) from the North Carolina Biotechnology Center. NTR: We thank the twins and their family members for their participation. Dunedin study: We thank the Dunedin Study members, unit research staff, and study founder Phil Silva. E-Risk study: We thank the study families for their participation and members of the E-Risk team for their dedication, hard work, and insights. The HumanMethylation450K BeadChip and RNA sequencing data from the BIOS Consortium are available in the European Genome-phenome Archive, under accession code EGAD00010000887. Data from the Dunedin Multidisciplinary Health and Development are available via a managed access system (contact: [email protected]). The HumanMethylation450K BeadChip DNA methylation data from the E-Risk study are available in Gene Expression Omnibus under accession number GSE105018. BF has received educational speaking fees from Shire and MEDICE. The other authors report no biomedical financial interests or potential conflicts of interest. NTR: NTR was supported by Biobanking and Biomolecular Research Infrastructure, the Netherlands (BBMRI-NL), Netherlands Organisation for Scientific Research ( NWO) 480-15-001/674 , Netherlands Twin Registry Repository : researching the interplay between genome and environment ( NWO 184.021.007 ), and Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies (ACTION). ACTION receives funding from the European Union Seventh Framework Program ( FP7/2007-2013 ) (Grant No. 602768 ). NTR was also supported by the Royal Netherlands Academy of Science Professor Award (Grant No. PAH/6635 to DIB), Netherlands Organization for Scientific Research (Vici Grant No. 016-130-669 to BF), Dutch National Science Agenda for the NWANeurolabNL project (Grant No. 400 17 602 to BF), European Community FP7 (Grant No. 602805 [Aggressotype] to BF), and European Community Horizon 2020 Program ( H2020/2014–2020 ) (Grant No. 728018 [Eat2beNICE] to BF). E-Risk study: The E-Risk study was supported by the Medical Research Council (Grant No. G1002190 ), National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant No. HD077482 ), American Asthma Foundation Distinguished Investigator Award (to JM), Jacobs Foundation, Avielle Foundation, Economic and Social Research Council Mental Health Leadership Fellowship (to LA), and Medical Research Council Skills Development Fellowship (to JA-B). This work used a high-performance computing facility partially supported by Grant No. 2016-IDG-1013 (“HARDAC+: Reproducible HPC for Next-generation Genomics”) from the North Carolina Biotechnology Center .

Funders	Funder number
Ministry of Business, Innovation and Employment
National Institute of Child Health and Human Development
Shire
MEDICE
National Institutes of Health
Health Research Council of New Zealand
BBMRI-NL
FP7/2007-2013
Avielle Foundation
Seventh Framework Programme
Aggression in Children
North Carolina Biotechnology Center
American Asthma Foundation
Medical Research Council	MR/P005918, G1002190, MR/P014100/1, MR/P005918/1
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	016-130-669, NWO) 480-15-001/674, 184.021.007, 480-15-001/674
Jacobs Foundation	2016-IDG-1013
Royal Netherlands Academy of Science	PAH/6635
European Commission	602768
National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development	HD077482
European Community Horizon 2020 Program	Eat2beNICE, H2020/2014–2020
National Institute on Aging	R01AG032282
Dutch National Science Agenda	400 17 602
Seventh Framework Programme	602805, 728018
Economic and Social Research Council	ES/P010113/1
UK Research and Innovation	ES/K000357/1
Eunice Kennedy Shriver National Institute of Child Health and Human Development	R01HD077482
Economic and Social Research Council Mental Health Leadership	GSE105018, EGAD00010000887
National Institutes of Health National Institute of Aging	R01AG032282

Cohort Studies

Netherlands Twin Register (NTR)

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10.1016/j.biopsych.2019.02.016

Persistent URL (handle)

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Cite this

van Dongen, J., Zilhão, N. R., Sugden, K., Hannon, E. J., Mill, J., Caspi, A., Agnew-Blais, J., Arseneault, L., Corcoran, D. L., Moffitt, T. E., Poulton, R., Franke, B., Boomsma, D. I., & BIOS Consortium (2019). Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults. Biological Psychiatry, 86(8), 599-607. https://doi.org/10.1016/j.biopsych.2019.02.016

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title = "Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults",

abstract = "BACKGROUND: Previous studies have reported associations between attention-deficit/hyperactivity disorder symptoms and DNA methylation in children. We report the first epigenome-wide association study meta-analysis of adult attention-deficit/hyperactivity disorder symptoms, based on peripheral blood DNA methylation (Infinium HumanMethylation450K array) in three population-based adult cohorts.METHODS: An epigenome-wide association study was performed in the Netherlands Twin Register (N = 2258, mean age 37 years), Dunedin Multidisciplinary Health and Development Study (N = 800, age 38 years), and Environmental Risk Longitudinal Twin Study (N = 1631, age 18 years), and results were combined through meta-analysis (total sample size N = 4689). Region-based analyses accounting for the correlation between nearby methylation sites were also performed.RESULTS: One epigenome-wide significant differentially methylated position was detected in the Dunedin study, but meta-analysis did not detect differentially methylated positions that were robustly associated across cohorts. In region-based analyses, six significant differentially methylation regions (DMRs) were identified in the Netherlands Twin Register, 19 in the Dunedin study, and none in the Environmental Risk Longitudinal Twin Study. Of these DMRs, 92\% were associated with methylation quantitative trait loci, and 68\% showed moderate to large blood-brain correlations for DNA methylation levels. DMRs included six nonoverlapping DMRs (three in the Netherlands Twin Register, three in the Dunedin study) in the major histocompatibility complex, which were associated with expression of genes in the major histocompatibility complex, including C4A and C4B, previously implicated in schizophrenia.CONCLUSIONS: Our findings point at new candidate loci involved in immune and neuronal functions that await further replication. Our work also illustrates the need for further research to examine to what extent epigenetic associations with psychiatric traits depend on characteristics such as age, comorbidities, exposures, and genetic background.",

author = "\{van Dongen\}, Jenny and Zilh{\~a}o, \{Nuno R\} and Karen Sugden and Hannon, \{Eilis J\} and Jonathan Mill and Avshalom Caspi and Jessica Agnew-Blais and Louise Arseneault and Corcoran, \{David L\} and Moffitt, \{Terrie E\} and Richie Poulton and Barbara Franke and D.I. Boomsma and \{BIOS Consortium\}",

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van Dongen, J, Zilhão, NR, Sugden, K, Hannon, EJ, Mill, J, Caspi, A, Agnew-Blais, J, Arseneault, L, Corcoran, DL, Moffitt, TE, Poulton, R, Franke, B, Boomsma, DI & BIOS Consortium 2019, 'Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults', Biological Psychiatry, vol. 86, no. 8, pp. 599-607. https://doi.org/10.1016/j.biopsych.2019.02.016

TY - JOUR

T1 - Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults

AU - van Dongen, Jenny

AU - Zilhão, Nuno R

AU - Sugden, Karen

AU - Hannon, Eilis J

AU - Mill, Jonathan

AU - Caspi, Avshalom

AU - Agnew-Blais, Jessica

AU - Arseneault, Louise

AU - Corcoran, David L

AU - Moffitt, Terrie E

AU - Poulton, Richie

AU - Franke, Barbara

AU - Boomsma, D.I.

AU - BIOS Consortium

PY - 2019/10/15

Y1 - 2019/10/15

N2 - BACKGROUND: Previous studies have reported associations between attention-deficit/hyperactivity disorder symptoms and DNA methylation in children. We report the first epigenome-wide association study meta-analysis of adult attention-deficit/hyperactivity disorder symptoms, based on peripheral blood DNA methylation (Infinium HumanMethylation450K array) in three population-based adult cohorts.METHODS: An epigenome-wide association study was performed in the Netherlands Twin Register (N = 2258, mean age 37 years), Dunedin Multidisciplinary Health and Development Study (N = 800, age 38 years), and Environmental Risk Longitudinal Twin Study (N = 1631, age 18 years), and results were combined through meta-analysis (total sample size N = 4689). Region-based analyses accounting for the correlation between nearby methylation sites were also performed.RESULTS: One epigenome-wide significant differentially methylated position was detected in the Dunedin study, but meta-analysis did not detect differentially methylated positions that were robustly associated across cohorts. In region-based analyses, six significant differentially methylation regions (DMRs) were identified in the Netherlands Twin Register, 19 in the Dunedin study, and none in the Environmental Risk Longitudinal Twin Study. Of these DMRs, 92% were associated with methylation quantitative trait loci, and 68% showed moderate to large blood-brain correlations for DNA methylation levels. DMRs included six nonoverlapping DMRs (three in the Netherlands Twin Register, three in the Dunedin study) in the major histocompatibility complex, which were associated with expression of genes in the major histocompatibility complex, including C4A and C4B, previously implicated in schizophrenia.CONCLUSIONS: Our findings point at new candidate loci involved in immune and neuronal functions that await further replication. Our work also illustrates the need for further research to examine to what extent epigenetic associations with psychiatric traits depend on characteristics such as age, comorbidities, exposures, and genetic background.

AB - BACKGROUND: Previous studies have reported associations between attention-deficit/hyperactivity disorder symptoms and DNA methylation in children. We report the first epigenome-wide association study meta-analysis of adult attention-deficit/hyperactivity disorder symptoms, based on peripheral blood DNA methylation (Infinium HumanMethylation450K array) in three population-based adult cohorts.METHODS: An epigenome-wide association study was performed in the Netherlands Twin Register (N = 2258, mean age 37 years), Dunedin Multidisciplinary Health and Development Study (N = 800, age 38 years), and Environmental Risk Longitudinal Twin Study (N = 1631, age 18 years), and results were combined through meta-analysis (total sample size N = 4689). Region-based analyses accounting for the correlation between nearby methylation sites were also performed.RESULTS: One epigenome-wide significant differentially methylated position was detected in the Dunedin study, but meta-analysis did not detect differentially methylated positions that were robustly associated across cohorts. In region-based analyses, six significant differentially methylation regions (DMRs) were identified in the Netherlands Twin Register, 19 in the Dunedin study, and none in the Environmental Risk Longitudinal Twin Study. Of these DMRs, 92% were associated with methylation quantitative trait loci, and 68% showed moderate to large blood-brain correlations for DNA methylation levels. DMRs included six nonoverlapping DMRs (three in the Netherlands Twin Register, three in the Dunedin study) in the major histocompatibility complex, which were associated with expression of genes in the major histocompatibility complex, including C4A and C4B, previously implicated in schizophrenia.CONCLUSIONS: Our findings point at new candidate loci involved in immune and neuronal functions that await further replication. Our work also illustrates the need for further research to examine to what extent epigenetic associations with psychiatric traits depend on characteristics such as age, comorbidities, exposures, and genetic background.

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DO - 10.1016/j.biopsych.2019.02.016

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Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults

Abstract

Bibliographical note

Funding

Cohort Studies

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